Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by physiologic restriction and progressive, ultimately fatal, respiratory failure. These functional changes are caused by fibrotic interstitial remodeling, alveolar destruction, and bronchiolization or “honeycombing” of the distal airspaces. IPF affects almost 0.5% of the US population over the age of 65, and its prevalence is increasing (1). The strongest risk predictor for developing IPF is the minor allele of the polymorphism rs35705950, a promoter variant upstream of the polymeric mucin MUC5B (2, 3). Variant rs35705950 is associated with increased MUC5B expression, suggesting that excessive MUC5B protein may play a role in the pathobiology of IPF. MUC5B is a dominant feature of human honeycomb cysts (HCs)(4, 5), which are composed of a stratified columnar epithelium comprising mucus and ciliated cells over a layer of cytokeratin 5 (KRT5)-expressing basal cells. We hypothesized that MUC5B was involved in HC formation.

Recently it was reported that influenza A infection (H1N1) promotes structural remodeling consistent with HCs in mice (6). Formation of these structures is contingent on mobilization of progenitor “pods” of Krt5-expressing cells (5–7). Using a previously published RNA sequencing Gene Expression Omnibus data set (GSE83467) comparing unstimulated murine progenitors to mobilized Krt5-expressing cells, we found that Muc5b was upregulated in Krt5 cells after H1N1 infection (fold change= 4.59; 95% confidence interval, 4.58–4.60; two biological replicates). We suspected that Muc5b might also be a feature of murine HCs. Given our recent findings that Muc5b modulates fibrosis in bleomycin-treated mice (8), we additionally wanted to determine whether honeycombing could be detected after bleomycin injury, and whether this was dependent on Muc5b.